The placenta, transfer of immunoglobulins, and safety assessment of biopharmaceuticals in pregnancy

Abstract

Anatomical and developmental differences of the parental–offspring interface among experimental animals and humans throughout gestation are reviewed focusing on biodistribution of immunoglobulins (IgG). The formation of the extraembryonic membranes, uteroplacental circulation, and characteristics of the placenta (gross shape, modes of implantation, surface modifications that increase surface area, and extent of embryonic invasion into maternal tissue) are reviewed. Placental physiology and function are covered with attention to transfer of xenobiotics. Placental transfer of immunoglobulins in the human, non-human primate (NHP), rodent, and rabbit is discussed and the transfer of human fragment crystallizable (Fc)-containing biopharmaceuticals and potential impact on developmental toxicity risk assessment are specifically addressed. Safety assessment is often limited to the NHP as the only pharmacologically relevant model, despite poor statistical power as employed in current experimental designs. Although data are limited, the gestational timing of placental IgG transfer in rabbits appears to be more consistent with that of humans (i.e. occurring at the very end and after completion of organogenesis) than that of rodents, making the rabbit a reasonable choice assuming it is pharmacologically relevant. The rodent is not considered the most appropriate model for human placental transfer of Fc-containing biopharmaceuticals because it is currently believed to overestimate exposure during organogenesis. Nevertheless, the rodent may provide a conservative approach for hazard identification. It is clear that additional experimentation is needed to further clarify the timing of prenatal transfer of Fc-containing biopharmaceuticals in various species.

Keywords:

• Placenta
• Placental transfer
• IgG
• Biopharmaceutical safety
• Fc receptors

Acknowledgements

The authors wish to thank Messrs. Jason Pope and Ken Arevalo for creating the diagrams in this paper, Ms. Arthi Venkat for creative input to the design of some figures, and Dr. Gregg Cappon for his expert review.

Declaration of interest

The employment of the authors is disclosed on the cover page. Exponent is a consulting firm that provides scientific analysis and advice in areas that include toxicology and risk assessment; Georgetown University School of Medicine is a provider of medical education; Pfizer Inc. is a developer and manufacturer of pharmaceutical products. Funding for this work was supplied by Exponent and Pfizer, Inc. The authors are solely responsible for the analyses and preparation of this manuscript; the opinions and conclusions are those of the authors and are not necessarily those of the sponsoring entities.

Notes

¹Interestingly, albumin levels are reported to be significantly reduced (approximately 32%) in FcRn-/- fetuses compared to both FcRn+/- and FcRn+/+ fetuses (Kim et al., 2009). Because FcRn plays pivotal roles in both mediating gestational transfer and controlling IgG and albumin catabolism, this reduction could be due to either diminished maternal-fetal transfer of albumin or increased catabolism of fetally produced albumin. More data is required, however, as neither the possible transport of albumin from mother to fetus nor the fetal tissue expression of FcRn have been examined in detail.

²Note that transcytosis across syncytiotrophoblast occurs as an ancillary mode of transport; hemotrophic exchange between maternal and fetal blood is highly efficient and is the predominant mode of transport.